Axon terminals are the conventional structures in the brain that release neurotransmitters and ensure communication between neurons. Dendrites, which are the typical postsynaptic component of the synapse, are nevertheless able to release neurotransmitters. In particular, dendrites in the substantia nigra pars compacta (SNc) release dopamine in a manner regulated by incoming neuronal activity and neuromodulators. The goal of this proposal is to investigate the mechanisms of dopamine dendritic release, when triggered by a physiological input from the subthalamus. A combination of techniques will be used which include patch-clamp recordings of neurons, maintained in slices or freshly isolated, and tyrosine hydroxylase immunostaining. The specific aims are i) to establish the existence of monosynaptic connections between subthalamic neurons and dopaminergic SNc neurons, ii) to demonstrate that the dendritic release of dopamine occurs upon stimulation of subthalamic afferents, iii) to clarify the role of the dopamine transporter in mediating such release, and finally iv) to investigate how dopamine controls subthalamic neuron excitability and enhances the potential excitotoxicity of their connection with SN dopaminergic neurons. Subthalamic neurons are hyperactive in Parkinson's patients and their lesion dramatically improves the symptoms of the disease. There is little doubt that the proposed studies focus on mechanisms likely to be involved in the onset and progression of Parkinson's disease.